Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema

Pappalardo, Emanuela; Cicardi, Marco; Duponchel, Christiane; Carugati, A.; Choquet, Sylvain; Agostoni, A; Tosi, Mario

doi:10.1067/mai.2000.110471

Cited by 211 publications

(149 citation statements)

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“…The allelic frequencies for g.14011a/g and p.V458M polymorphisms, respectively, do not differ significantly from those reported in Caucasians earlier by Verpy et al, 1996 (p = 0,058 and p = 0,398, respectively; chi-squared test) , but g.14011a variant tends to be more frequent in our population. It was previously suggested that the sequence variation g.566T/C represents a mutation or polymorphism probably having no effect on the transcript or the protein, since it was associated with causative mutations and is located to 5' untranslated region of the C1NH gene (Verpy et al, 1996 andPappalardo et al, 2000). We have indeed detected this polymorhism in 4 out of 50 individuals in the general population (data not shown).…”

Section: Resultssupporting

confidence: 64%

“…A sequencing revealed at least one sequence variation in each PCR product giving a positive result on DGGE. Single strand conformational polymorphism (SSCP) and fluoresence assisted mismatch analysis (FAMA) are usually used to search for mutations in the C1NH gene, with the exception of large gene rearrangements which are being detected with Southern blots or fluorescent multiplex PCR (Verpy et al, 1996;Bissler et al, 1997;Zuraw and Herschbach, 2000;Pappalardo et al, 2000;Stoppa-Lyonet et al, 1990, Duponchel et al, 2001. We have established and present in this report that denaturing gradient gel electrophoresis is an efficient, alternative method for screening of point mutations and small deletions or insertions.…”

Section: Resultsmentioning

confidence: 99%

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Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema

et al. 2002

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Hereditary angioedema (HAE) is a disorder characterised by recurrent attacks of localized subcutaneous or submucosal edema. It is inherited in an autosomal dominant fashion and caused by a deficiency of C1 inhibitor (C1 inh, or C1NH). Most patients with HAE have an absolute deficiency of C1 inh (type I HAE) while the rest (15% of kindreds) synthetize a dysfunctional C1 inh protein (type II HAE).In this report a novel use of denaturing gradient gel electrophoresis (DGGE) followed by direct sequencing of the C1 inhibitor gene is presented. Five novel mutations, one nonsense (p.S48X) and four small deletions resulting in frameshifts (g.2264-2265delAG, g.2304delC, g.8493-8494delCC and g.16676-16677delTG) have been identified in the C1 inhibitor gene in five families with type I HAE. All of these mutations lead to premature termination of translation and thus can be considered causative of the C1 inh deficiency. Moreover, two previously described mutations in the reactive center of C1 inh, p.R444C and p.R444H, have been detected in four unrelated patients with type II HAE.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema

et al. 2002

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“…If C1‐INH‐HAE is suggested by testing, then all first‐degree relatives in the ascending line should be screened (including symptom‐free individuals). As with many autosomal dominant disorders, 25% of cases may be a de novo mutation which may then be passed onto future descendants 76. SERPING1 gene sequencing may be helpful to confirm the C1‐INH‐HAE in this setting 64, 66.…”

Section: Resultsmentioning

confidence: 99%

International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

Farkas

Martinez‐Saguer²,

Bork

et al. 2016

Allergy

172

308

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BackgroundThe consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1‐INH‐HAE.MethodsDuring an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.ResultsThe symptoms of C1‐INH‐HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1‐INH‐HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1‐INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1‐INH‐HAE family member should be screened for C1‐INH deficiency. Pediatric patients should always carry a C1‐INH‐HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma‐derived C1‐INH, recombinant C1‐INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.ConclusionsThe pediatric‐focused international consensus for the diagnosis and management of C1‐INH‐HAE patients was created.

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“…According to the antigenic plasma level of the C1INH protein, two types of HAE are distinguished: a quantitative defect (type I) in which the protein level is low, and a qualitative defect (type II), which is less frequent and characterized by decreased functional activity, in spite of normal or even high antigenic levels [Rosen et al, 1971]. The high incidence of de novo mutations (~25%) [Verpy et al, 1996, Pappalardo et al, 2000, and the variability of C1INH protein levels in young subjects underscore the importance of DNA assays to provide direct and rapid diagnosis for suspected HAE-cases. Furthermore, identification of previously unreported C1INH mutations may provide useful data for structure-function relationship analyses.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema

Kalmár¹,

Bors²,

Farkas

et al. 2003

Hum. Mutat.

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Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema caused by the deficiency of activated C1 esterase inhibitor protein (C1-INH, type I (C1NH): reduced serum antigen level, type II: reduced activity and normal serum antigen level). The aim of the present study was to determine the disease-causing mutations in the C1INH gene (SERPING1) among Hungarian HAE-patients. The estimated number of affected HAE-families in Hungary is 40-50, out of which 26 families (type I:23, type II:3) managed in a single center were enrolled in the current study. To detect large deletions/insertions, we used Southern-blotting analysis followed by real time PCR based gene dosage analysis. In the absence of large structural changes, we employed direct sequencing covering the whole coding region and splicing sites of the C1INH gene. Large deletions were detected in 4/23 (17.4%) type I families. We found the g.16788C>T (p.Arg444Cys) mutation in each 3, type II HAE-families. In the remaining type

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Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema

Cited by 211 publications

References 20 publications

Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema

Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema

International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency

Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema

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